6f8v: Difference between revisions
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==Crystal structure of the PDE4D catalytic domain in complex with GEBR-18b== | |||
<StructureSection load='6f8v' size='340' side='right' caption='[[6f8v]], [[Resolution|resolution]] 1.85Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6f8v]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F8V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F8V FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D0B:3-[3-(3-cyclopentyloxy-4-methoxy-phenyl)pyrazol-1-yl]-1-[(2~{R},6~{R})-2,6-dimethylmorpholin-4-yl]propan-1-one'>D0B</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3',5'-cyclic-AMP_phosphodiesterase 3',5'-cyclic-AMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.53 3.1.4.53] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6f8v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f8v OCA], [http://pdbe.org/6f8v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f8v RCSB], [http://www.ebi.ac.uk/pdbsum/6f8v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f8v ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/PDE4D_HUMAN PDE4D_HUMAN]] Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. Defects in PDE4D are the cause of acrodysostosis type 2, with or without hormone resistance (ACRDYS2) [MIM:[http://omim.org/entry/614613 614613]]. ACRDYS2 is a pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems.<ref>PMID:22464250</ref> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/PDE4D_HUMAN PDE4D_HUMAN]] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.<ref>PMID:15260978</ref> <ref>PMID:15576036</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Selected members of the large rolipram-related GEBR family of type 4 phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term potentiation and to improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, few if any structure-activity relationship studies have been performed to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone. Furthermore, we assessed the stability of the observed ligand conformations in the context of the intact enzyme using molecular dynamics simulations. The longer and more flexible ligands appear to be capable of forming contacts with the regulatory portion of the enzyme, thus possibly allowing some degree of selectivity between the different PDE4 isoforms. | |||
Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds.,Prosdocimi T, Mollica L, Donini S, Semrau MS, Lucarelli AP, Aiolfi E, Cavalli A, Storici P, Alfei S, Brullo C, Bruno O, Parisini E Biochemistry. 2018 May 15;57(19):2876-2888. doi: 10.1021/acs.biochem.8b00288., Epub 2018 May 1. PMID:29652483<ref>PMID:29652483</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6f8v" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: 3',5'-cyclic-AMP phosphodiesterase]] | |||
[[Category: Donini, S]] | [[Category: Donini, S]] | ||
[[Category: Parisini, E]] | [[Category: Parisini, E]] | ||
[[Category: Prosdocimi, T]] | [[Category: Prosdocimi, T]] | ||
[[Category: Catalytic domain]] | |||
[[Category: Gebr]] | |||
[[Category: Hydrolase]] | |||
[[Category: Inhibitor]] | |||
[[Category: Pde4]] | |||